Affiliation:
1. From the Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Md.
Abstract
Rationale:
Sinoatrial node cells (SANCs) generate local, subsarcolemmal Ca
2+
releases (LCRs) from sarcoplasmic reticulum (SR) during late diastolic depolarization. LCRs activate an inward Na
+
-Ca
2+
exchange current (
I
NCX
), which accelerates diastolic depolarization rate, prompting the next action potential (AP). The LCR period, ie, a delay between AP-induced Ca
2+
transient and LCR appearance, defines the time of late diastolic depolarization
I
NCX
activation. Mechanisms that control the LCR period, however, are still unidentified.
Objective:
To determine dependence of the LCR period on SR Ca
2+
refilling kinetics and establish links between regulation of SR Ca
2+
replenishment, LCR period, and spontaneous cycle length.
Methods and Results:
Spontaneous APs and SR luminal or cytosolic Ca
2+
were recorded using perforated patch and confocal microscopy, respectively. Time to 90% replenishment of SR Ca
2+
following AP-induced Ca
2+
transient was highly correlated with the time to 90% decay of cytosolic Ca
2+
transient (T-90
C
). Local SR Ca
2+
depletions mirror their cytosolic counterparts, LCRs, and occur following SR Ca
2+
refilling. Inhibition of SR Ca
2+
pump by cyclopiazonic acid dose-dependently suppressed spontaneous SANCs firing up to ≈50%. Cyclopiazonic acid and graded changes in phospholamban phosphorylation produced by β-adrenergic receptor stimulation, phosphodiesterase or protein kinase A inhibition shifted T-90
C
and proportionally shifted the LCR period and spontaneous cycle length (
R
2
=0.98).
Conclusions:
The LCR period, a critical determinant of the spontaneous SANC cycle length, is defined by the rate of SR Ca
2+
replenishment, which is critically dependent on SR pumping rate, Ca
2+
available for pumping, supplied by L-type Ca
2+
channel, and ryanodine receptor Ca
2+
release flux, each of which is modulated by cAMP-mediated protein kinase A–dependent phosphorylation.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
75 articles.
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